Dronedarone

CrCl (mL/min)	Dosage
<30	Contraindicated.

Severe: Contraindicated.

Should be taken with food. Avoid grapefruit juice.

Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored); symptomatic heart failure with recent decompensation requiring hospitalisation or NYHA class IV heart failure, left ventricular systolic dysfunction; complete bundle branch block, distal block, sinus node dysfunction, atrial conduction defects, 2nd- or 3rd-degree AV block or sick sinus syndrome (unless a functioning pacemaker is present); bradycardia (heart rate <50 bpm); liver and lung toxicity associated with previous amiodarone use; QTc Bazett interval ≥500 milliseconds or PR interval >280 milliseconds; unstable haemodynamic conditions. Concomitant use with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, telithromycin, clarithromycin, nefazodone, ritonavir, ciclosporin), agents known to prolong QT interval and may induce torsades de pointes (e.g. phenothiazines, TCAs, certain oral macrolides, class I and III antiarrhythmics, bepridil, cisapride, terfenadine), and dabigatran. Severe renal (CrCl <30 mL/min) and hepatic impairment.

Patient with CAD, electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia). Mild to moderate hepatic impairment. Elderly. Not recommended during pregnancy. Lactation.

Significant: New-onset or worsening heart failure; marked increase in serum creatinine, pre-renal azotaemia, acute renal failure; QTc interval prolongation; interstitial lung disease (including pneumonitis and pulmonary fibrosis).
Cardiac disorders: Bradycardia.
Gastrointestinal disorders: Diarrhoea, vomiting, nausea, abdominal pain, dyspepsia, dysgeusia.
General disorders and administration site conditions: Fatigue, asthenia.
Investigations: Abnormal LFTs.
Skin and subcutaneous tissue disorders: Rash (generalised, macular, maculopapular and erythematous rash), pruritus, eczema, dermatitis, photosensitivity reaction.
Potentially Fatal: Hepatocellular injury, including acute hepatic failure.

PO: Z (Embryo-foetal mortality and malformations were observed in animal studies. Not recommended during pregnancy.)

Women of childbearing potential must use effective birth control methods during treatment and for 7 days after the last dose. Breastfeeding is not recommended during treatment and for 7 days after the last dose.

Verify pregnancy status before initiating treatment. Correct hypokalaemia or hypomagnesaemia prior to initiation and during treatment. Perform LFTs prior to and periodically during treatment (particularly in the 1st 6 months), and if liver injury is suspected; ECG at least every 3 months. Monitor blood pressure, heart rate; serum electrolytes (particularly K and Mg); serum creatinine (prior to treatment and 7 days after initiation). Assess for signs and symptoms of new or worsening heart failure (e.g. breathlessness, dependent oedema, weight gain); pulmonary toxicity (e.g. dyspnoea, non-productive cough); liver injury (e.g. jaundice, dark urine, anorexia, abdominal pain).

May increase the serum concentrations of digoxin, statins (e.g. simvastatin and simvastatin acid, lovastatin, atorvastatin), tacrolimus, sirolimus, everolimus, rivaroxaban, apixaban, warfarin and other vitamin K antagonists, Ca channel blockers (e.g. verapamil, diltiazem), and β-blockers (e.g. metoprolol, propranolol). Decreased serum concentration with CYP3A4 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin). Increased serum concentration with Ca channel blockers (e.g. verapamil, diltiazem) or other moderate CYP3A4 inhibitors. Concomitant use with K-depleting diuretics may result in hypokalaemia or hypomagnesaemia.
Potentially Fatal: Significantly increased dronedarone exposure with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, telithromycin, clarithromycin, nefazodone, ritonavir, ciclosporin). May increase the risk of torsades de pointes with agents that prolong the QT interval (e.g. phenothiazines, TCAs, certain oral macrolides [e.g. erythromycin], class I and III antiarrhythmic agents, bepridil, cisapride, terfenadine). Increases the serum concentration of dabigatran.

Increased bioavailability with food. Increased serum concentration with grapefruit juice. May decrease serum concentration with St. John's wort.

Description:
Mechanism of Action: Dronedarone is a noniodinated antiarrhythmic agent that is reported to have properties of all 4 Vaughan-Williams classes, but the exact contribution of each of these activities to the clinical effect is unknown. It inhibits K channels resulting in prolongation of the cardiac action potential and refractory periods. Additionally, it inhibits Na currents and Ca channels and demonstrates non-competitive antiadrenergic activities.
Pharmacokinetics:
Absorption: Bioavailability: 4% (without food); 15% (with food). Time to peak plasma concentration: 3-6 hours (fed conditions).
Distribution: Plasma protein binding: >98%, mainly to albumin.
Metabolism: Extensively metabolised in the liver mainly by CYP3A4 to a less active N-debutyl metabolite; initial metabolic pathway includes N-debutylation to form the active metabolite, oxidative deamination to form the inactive propanoic acid metabolite and direct oxidation. Undergoes extensive first-pass metabolism.
Excretion: Via faeces (84%, mainly as metabolites); urine (approx 6% as metabolites). Elimination half-life: Approx 25-30 hours (dronedarone); approx 20-25 hours (N-debutyl metabolite).

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 208898, Dronedarone. https://pubchem.ncbi.nlm.nih.gov/compound/Dronedarone. Accessed Nov. 27, 2024.

Store between 15-30°C.

Cardiac Drugs

C01BD07 - dronedarone ; Belongs to class III antiarrhythmics.

Anon. Dronedarone. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 01/10/2024.

Brayfield A, Cadart C (eds). Dronedarone. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/10/2024.

Dronedarone Aristo 400 mg Film-coated Tablets (Aristo Pharma GmbH). MHRA. https://products.mhra.gov.uk. Accessed 01/10/2024.

Dronedarone. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 01/10/2024.

Joint Formulary Committee. Dronedarone. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/10/2024.

Multaq 400 mg Film-coated Tablets (Sanofi Hong Kong Limited). MIMS Hong Kong. http://www.mims.com/hongkong. Accessed 12/11/2024.

Multaq 400 mg Film-coated Tablets (Sanofi Winthrop Industrie). European Medicines Agency [online]. Accessed 29/11/2024.

Multaq Tablet, Film Coated (Sanofi-Aventis U.S. LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 13/11/2024.